Disorders of globin synthesis

Question 1

Describe normal adult hemoglobin

Answer 1

HbA, 2 alpha and 2 beta chains

Question 2

Describe the composition of fetal hemoglobin, HbF

Answer 2

2 alpha and 2 gamma chains

Question 3

Describe the composition of hemoglobin A2

Answer 3

HbA2, 2 alpha and 2 delta chains

Question 4

There are two copies of the ____ gene on chromosome 16 and one __ gene as well as the gamma gene on chromosome 11

Answer 4

alpha on chromosome 16

beta on chromosome 11

Question 5

In normal diploid cells, there are ____ alpha genes, __ beta genes, ___ delta genes, and ____ gamma genes

Answer 5

4 alpha, 2 beta, 2 delta, 4 gamma

Question 6

The switch from Hb_ to Hb_ occurs at about six months of life

Answer 6

HbF–> HbA

Question 7

Differentiate hemoglobinopathy from thalassemia syndromes

Answer 7

Hemoglobinopathy: inherited mutation of a globin gene that causes a qualitative abnormality of a globin chain. causes hemoglobin to polymerize, crystalize, or denature

Thalassemia: quantitative defect in globin syntehsis that results in imbalanced production of globin subunits, decreased production of either a or B. Excess unaffected globin can attahc to and damage the RBC membrane leading to destruction of precursors in the marrow or periphery

Question 8

Thalassmeias can lead to destruction of RBCs by _________ in the marrow or _____ in the periphery

Answer 8

ineffective erythropoeisis

hemolysis

Question 9

What type of hemoglobin can be missed on standard electrophoresis and why?

Answer 9

Barts hemoglobin (gamma4) because it is unstable and migrates rapidly. it is formed when there is decreased or absent a globin production

Question 10

List the three most common genotypes that produce sickle cell disease

Answer 10

BS/BS
BS/B0
BS/ BC

Question 11

In sickle cell anemia, there is a ______ residue insetead of ____ in the 6th position of the beta globin gene

Answer 11

valine instead of glutamic acid

Question 12

As HbS ______, it distorts and dehydrates the RBC causing sickling

Answer 12

polymerizes

Question 13

Damage to the RBC membrane in sickle cell anemia disrupts cation homeostasis, reducing the ability of the cell to maintain a normal ____ gradient

Answer 13

K

Question 14

Describe how higher levels of HbF are helpful for patients with sickle cell anemia

Answer 14

HbF in a cell inhibits HbS polymerization, thus decreases the likelihood of sickling. Associated with less severe disease

Question 15

Describe the effects of sickle cells on NO

Answer 15

Hemolysis of sickled cells in the microvasculature releases heme into the plasma, which consumes NO
Hemolyzed RBCs also release arginase, which destroys arginine (a precursor for NO)

Question 16

List how chronic depletion of NO leads to vasculopathy in sickle cell disease

Answer 16

• vasoconstriction
• increased platelet aggregation
• endothelial activation

Question 17

List factors that exacerbate sickling

Answer 17

anything that increases the percentage of deoxyhemoglobin in the cell (causes a right shift in oxygenation curve): acidosis, increased 2,3 DPG, etc

Question 18

List three major categories of complications of sickle cell disease

Answer 18

1. hemolytic anemia
2. vaso-occlusion (pain syndromes, acute organ damage, chronic organ damage)
3. susceptibility to infection

Question 19

The hemolysis of sickle cell anemia is mainly (extravascular/ intravascular)

Answer 19

extravascular (some intravascular occurs)

Question 20

List some complications seen in sickle cell anemia that are associated with the chronic hemolysis

Answer 20

risk of aplastic crisis with parvovirus infection, folate deficiency, bilirubin gallstones, iron overlaod

Question 21

Sickle cell disease patients with the highest rate of _____ have the highest reticulocyte count AND the highest vaso-occulsive risk. ____ count is a marker of chronic inflammation and higher level predicts greater vaso-occulsive risk

Answer 21

highest rate of hemolysis

associated with hgih neutrophils

Question 22

The earliest manifestation of painful crises in sickle cell disease is usually ____

Answer 22

dactylitis- painful swelling of hands and feet

Question 23

__________ is a vaso-occlusive complication that is life threatening, usually associated with infection, and characterized by tachypnea, hypoxia, pain, cough, and infiltrates on chest X ray

Answer 23

acute chest syndrome

Question 24

List treatment of acute chest syndrome

Answer 24

supplemental oxygen
transfusion or exchange
NO
bronchodilators
antibiotics

Question 25

Individuals identified as having a high risk of stroke by cranial Doppler study undergo __________ therapy

Answer 25

chronic transfusion therapy

Question 26

List some forms of chronic organ damage seen in sickle cell disease

Answer 26

Leg ulcers, osteonecrosis of the femoral head, pulmonary hypertension, chronic kidney disease, heart failure, retinal disease, and increased fetal loss during pregnancy

Question 27

Describe why patients with sickle cell disease are at risk of infection

Answer 27

Micro-occlusive events eventually lead to splenic ischemia and autosplenectomy, increases susceptibility to encapsulated organisms
Infarcted tissue is vulnerable to infection- often see Slamonella and Staphylococcal infections in bone

Question 28

Describe how treatment with hydroxyurea provides improvement for patients with sickle cell disease

Answer 28

increase HbF production, decrease inflammation, affect cell-cell interactions, and improve the hydration status of the red cell

Clinical results: children retain splenic function longer, better growth curves, fewer vaso-occlusive events, slightly higher Hb
Adults have improved QoL

Question 29

The only curative treatment for sickle cell disease is ________

Answer 29

bone marrow transplant

Question 30

List an iron chelating agent used in sickle cell disease and its purpose

Answer 30

deferoxamine, given intravenously, or deferasirox, given orally
may decrease the incidence of end organ failure due to iron overload.

Question 31

What findings could be present in a person with sickle trait

Answer 31

failure to concentrate urine and possible painless hematuria- renal medulla is hypoxic, acidotic, and hyperosmolar which promotes sickling

may have sickling in severe dehydration, travel to very high altitudes

Question 32

Describe hemoglobin C

Answer 32

Lysine replaces glutamic acid in the 6th position of the beta globin gene
Homozygocity results in mild microcytic hemolytic anemia
Many target cells on smear with rare hemoglobin crystals
Compound heterozygosity: BS/BC- cells do sickle, generally milder than S/S disease

Question 33

Describe hemoglobin E

Answer 33

Hemoglobin mutation that cause decreased production of normal beta globin (acts like a thalassemia)
Common in SE Asian populations
Heterozygotes and homozygotes have very mild anemia, but can have compound heterozygosity with B thalassemia which can be severe

Question 34

List three mechanisms of anemia in thalassemia

Answer 34

ineffective erythropoiesis
hemolysis
decreased hemoglbin synthesis

Question 35

List the genotypes and clinical manifestations of a thalassemia carriers

Answer 35

a-/aa

Silent- no anemai

Question 36

List the genotypes and clinical manifestations of a thalassemia trait

Answer 36

a-/a- or –/aa

Mild microcytic anemia, no specific treatment, avoid iron supplements

Question 37

List the genotypes and clinical manifestations of HbH disease

Answer 37

a-/–

Moderate hemolytic anemia, treat with folic acid and avoid oxidant drugs. give transfusion/ splenectomy as needed

Question 38

List the genotypes and clinical manifestations of hydrops fetalis

Answer 38

–/–

lethal in utero

Question 39

List the genotypes and clinical manifestations of B thalassemia minor

Answer 39

B/B0 or B/B+
Mild microcytosis with or without anemia
No treatment, avoid iron supplements

Question 40

List the genotypes and clinical manifestations of B thalassemia intermedia

Answer 40

B+/B+ or B+/B0 or B/B0
Moderate to severe anemia
treat with folic acid, RBC transfusion or splenectomy as needed

Question 41

List the genotypes and clinical manifestations of B thalassemia major

Answer 41

B0/B0

Severe, transfusion dependent anemia with iron chelation therapy. Early referral for stem cell transplant

Question 42

In B thalassemia major, the only functional hemoglobins produced are ____ and _______

Answer 42

HbF: 2 alpha and 2 gamma
HbA2: 2 alpha and 2 delta

Question 43

In the a thalassemias, there is a high percentage of _______ heomglobin in the newborn

Answer 43

Bart’s hemoglobin- gamma4

Question 44

Describe hemoglobin H

Answer 44

B4, found in people with three deleted a genes